Aerosol type dispensers are used throughout the world for dispensing a wide range of products, for example hair lacquer, furniture polish, cleaners, paint, insect killers and medicaments.
Liquefied compressed gases are invariably used as the propellant for aerosol dispensers for inhalation therapy in preference to non-liquefied compressed gasses such as nitrogen or carbon dioxide, as they confer the following critical advantages:
a) the spray undergoes flash evaporation to give aerosols of very small particle size
b) the spray particle size remains constant during pack emptying as the inhaler vapour pressure is maintained at an almost constant level by progressive propellant evaporation
c) the pressure generated by partial evaporation of propellant in the valve metering chamber causes efficient discharging of the metered valve contents and accurate dose delivery
d) suitably designed formulations have notably good chemical drug stability and resistance to microbial growth.
FIGS. 1A and 1B of the accompanying drawings show the valve and lower portion of a typical MDI aerosol dispenser in closed and open positions respectively. Such dispensers generally comprise a small aluminium shuttle valve 1 which is crimp fitted to the can 2 containing the drug and chlorofluorocarbon (CFC) propellants. The valve is activated by manually pressing shuttle pin 3 such that it moves a small distance into the can 2. In order to do this it is necessary to overcome the force exerted on the pin 3 by virtue spring 4 and of the pressure within the container. Pressures within such dispensers are typically around 8 bar which is sufficient to maintain CFC propellants in a liquid state at ambient temperatures.
Until recently, CFCs were the most common of the propellant gases used in aerosols because they are inert, miscible with a wide range of products, are easily liquefied under low pressures, give a substantially constant product flow-rate, and can produce sprays of droplets having mean diameters in the range of 3 to over 100 micrometers. However, in the 1970""s it was proposed that CFCs were probably responsible for depleting the Earth""s protective ozone layer, and in 1987, most countries signed the Montreal Protocol to phase out the use of CFCs and have since agreed to stop use of CFCs for non-essential applications by the end of 1995. One notable exemption to this deadline for cessation of use is in relation to MDIs for medicaments, which are regarded as an essential use of CFCs, but even this use of CFCs will be phased out as acceptable alternatives are developed.
Many companies are now working to develop alternative CFCxe2x80x94free propellants for use in aerosol spray devices including MDIs to overcome the ozone destructing properties of conventional CFC containing propellants. A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional CFCs comprise fluorocarbons and hydrogen-containing fluorocarbons (commonly known as HFA propellants), and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example European Patent Application Publication No. 0372777 and PCT Patent Application Nos. WO91/04011, WO91111173, WO91/11495 and WO91114422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. The applications all propose the addition of one or more of adjuvents such as alcohols, alkanes, dimethyl, ether, surfactants and even conventional chlorofluorocarbon propellants in small amounts to minimise potential ozone damage. Surfactants are added to make the suspension formulations stable. However, whilst surfactants may conveniently be used in MDIs which use CFC propellants, surfactants are not generally solvent in HFA propellants and so require the use of additional co-solvents.
Attempts have also been made to develop devices which produce satisfactory spray characteristics making use of compressed gases such as nitrogen and carbon dioxide, which are present in the atmosphere in relatively large proportions. The main problem associated with aerosol dispensers of this type which use compressed gas propellant is that whilst the spray characteristics may be satisfactory when the dispenser is full and the propellant is at a high pressure, they display a serious drop in pressure during emptying as the available headspace increases with the result that the atomizing and spray pattern deteriorate to an extent that dispensing becomes unsatisfactory for many purposes. Such dispensers may be used where such deterioration of the atomization and spray pattern are of no concern, e.g. in the dispensing of foodstuffs, but it has not been found to be useful in areas where atomization and spray patterns are important, e.g. in dispensing of medicaments. For this latter application it is often required to deliver drugs to topically treat the lung or to provide a route for absorption into the blood stream of drugs that are poorly absorbed from the alimentary tract. To reach the alveoli it is essential that the aerodynamic size of the particles is less than 10 micrometers, preferably between 0.5 and 5 micrometers. In order to reliably reproduce aerosol sprays from a dispenser in which the majority of particles have a size of between 0.5 and 5 micrometers it is necessary to maintain a fairly constant propellant pressure.
The pressures that would be required to maintain gases such as carbon dioxide in a liquid state at ambient temperatures are typically of the order of 10 times greater than that within a conventional dispenser such as that shown in FIGS. 1A and 1B, and such pressures are far in excess of those within any dispensers currently available. Hence to maintain the same activation force, the shuttle pin diameter would need to be reduced accordingly resulting in more stringent engineering requirements.
U.S. Pat. No. 5,301,664 describes an apparatus for producing a gasborne dispersion of a physiologically active solute dissolved in a supercritical fluid solvent. The supercritical fluid solution is passed into a subcritical region to evaporate the solvent and form an aerosol cloud of the solute particles. Some of the problems associated with this device are that: (i) the temperature and pressure of the reservoir must be maintained above the critical temperature and pressure of the solvent in order to maintain supercritical conditions, and (ii) to ensure consistent delivery of solute dose upon each actuation of the valve it is necessary to either reduce the reservoir volume each time a dose is delivered by the magnitude of the volume dispensed to maintain solute density, or increase the dose size accordingly.
European Patent Application 675054 (published after the priority date of this application) describes a constant quantity injection valve and canister for carbon dioxide however it does not discuss the use of solutions or suspensions of substances in carbon dioxide, nor does it mention use of the valve in an apparatus for inhalation therapy. Furthermore, since opening of the valve requires the pressure inside the canister to be overcome, the arrangement is disadvantageous when the carbon dioxide is under very high pressure.
European Patent Application 677332 (published after the priority date of this application) describes a method and apparatus for producing fine particles of substance which comprises dissolving the substance in a first liquid, mixing the resultant solution with a second fluid (such as supercritical carbon dioxide) and then rapidly lowering the pressure. However this method may not be suitable for all substances and the apparatus is relatively complex since it requires control of a mixing step. Furthermore, if the solvent of the first liquid is itself soluble in the second fluid, the dissolved substance may start to recrystallise in an uncontrolled manner prior to the pressure being lowered.
European Patent Application 671218 describes a method of generating an aerosol using a liquefied gas propellant. Medical agents are described which are dissolved or suspended in a liquefied gas to be aerosolized, wherein the medical agents have a particle size of 0.5 xcexcm or below when suspended in the liquefied gas to be aerosolized.
It is an object of the present invention to provide a method and apparatus for generating aerosol mists which overcomes the aforementioned disadvantages or which is of more general application or which achieves the desired end with greater ease or simplicity.
According to the present invention there is provided a hand held apparatus for creating an aerosolised mist of particles, the apparatus comprising a high pressure vessel containing a solution or suspension of the substance to be aerosolised in a high pressure liquefied gas which is in a subcritical state, a manually actuatable valve and a spray nozzle.
We particularly envisage that the valve will be a metering valve. Thus, the valve may comprise a body having an inlet in communication with the high pressure vessel, an outlet in communication with the spray nozzle, and a metering member including a metering chamber mounted in the body which is adapted to move between a first position in which it is in communication with the inlet and a second position in which it is in communication with the outlet.
In a preferred embodiment of the invention, the metering member is defined by a shaft and the metering chamber is a cut-away section of the shaft. Thus the valve body is provided with a bore, the metering member is defined by a shaft, the metering chamber is a cut-away section of the shaft and the shaft is seated in the bore.
Preferably both ends of the bore will be open to the atmosphere.
In a particularly preferred embodiment of the invention the valve comprises a body with an inlet and an outlet, a shaft with a cut away section mounted in the body and moveable between a first position in which the cut away section is in communication with the inlet, and a second position in which the cut away section is in communication with the outlet, and wherein the shaft and inlet are arranged such that the force required to actuate the valve by movement of the shaft between the first and second positions is substantially independent of the pressure at the inlet.
Such an embodiment has the advantage that the user of the apparatus will not have any difficulty in causing actuation of the valve even when the pressure inside the high pressure vessel is very high. More particularly the pressure that can be tolerated inside the high pressure vessel is limited by the strength of that vessel and the operating parameters of the apparatus (for example the requirement to keep the gas in a sub-critical state) and not by the strength of the user. Furthermore, the manufacture of apparatus parts is not expected to cause any particular engineering difficulty.
In one convenient arrangement which has the advantage of symmetry and ease of manufacture, the shaft and inlet are arranged such that the valve is actuated by movement of the shaft between the first and second positions along an axis which is orthogonal to the axis along which the pressure at the inlet is exerted. In the above arrangements, seals will be disposed between the body and the shaft to prevent the escape of liquefied gas. Ideally, seals will be arranged such that the inlet is at all times isolated from the outlet irrespective of the position of the shaft. For example there may be disposed 2 pairs of seals such that when the metering chamber is in the first position a first pair of seals keeps the metering chamber in communication with the inlet and isolated from the outlet and when the metering chamber is in the second position a second pair of seals keeps the metering chamber in communication with the outlet and isolated from the inlet.
Although a number of alternatives can be envisaged, we find it useful to use polytetrafluoroethylene (PTFE) lip seals with an integral spring. PTFE is a particularly suitable sealing material because it does not absorb carbon dioxide, does not require lubrication, does not contain carcinogenic compounds and is food grade. PTFE is non-elastomeric and so requires an integral spring to maintain a seal. Alternative seal designs or materials, e.g. ultra-high molecular weight polyethylene, could also be used.
An alternative embodiment of the invention which does not have the advantage that the force required to actuate the valve by movement of the shaft between the first and second positions is substantially independent of the pressure at the inlet, but which does nonetheless have the advantage that the burden on the user to actuate the valve may be significantly eased is set out in the following embodiment.
In this embodiment, we provide an apparatus wherein the valve inlet is provided with a pin valve comprising a pin biased against a seat and the shaft includes a ramped surface such that in the first position the pin of the pin valve is displaced from its seat to allow communication between the high pressure vessel and the metering chamber and in the second position the pin of the pin valve is seated to prevent communication between the high pressure vessel and the metering chamber and wherein the displacement of the pin from its seat against the bias is caused by urging of the ramped surface against the pin upon movement of the shaft between the first and second positions.
The arrangement is especially convenient when the valve body is provided with a second outlet and when the shaft includes a second ramped surface which cooperates with the first ramped surface such that the shaft may move between the first position in which the metering chamber is in communication with the inlet and the second position in which the metering chamber is in communication with one of the two outlets on moving the shaft laterally in either direction within the bore.
The apparatus will also desirably be provided with seals which are arranged such that the inlet is at all times isolated from the outlet or outlets irrespective of the position of the shaft.
As a further improvement, the high pressure vessel may be provided with an integral valve assembly comprising a member biased against a seat such that when the high pressure vessel is engaged with the metering valve inlet the vessel valve member lies in close proximity to the pin of the metering valve pin valve such that on actuation of the metering valve the pin of the metering valve pin valve is pushed off its seat and abuts against the vessel valve member which is in turn pushed off its seat thereby bringing the inlet into communication with the interior of the vessel. The advantage of this arrangement is that the valve of the apparatus may readily be engaged and disengaged from the high pressure vessel thus facilitating replacement or renewal of the contents of the vessel.
According to another aspect of the invention there is also provided a method for creating an aerosolised mist of particles which comprises forming a solution or suspension of the substance to be aerosolised in a high pressure liquefied gas which is in a sub-critical state and rapidly expanding the solution or suspension at the spray nozzle of an apparatus according to the invention.
As a consequence of using a high pressure liquefied gas, the propellant will flash off from the droplets more rapidly than conventional propellants thereby decreasing the likelihood that drug laden droplets will impact on the throat of the patient and, as a consequence, increase the efficiency with which drug is delivered to the lungs.
High-pressure liquefied gases will typically be those that liquefy at ambient temperature at a pressure of greater than 25 bar. More usually they will liquefy at a pressure in excess of 55 bar and may be up to 150 bar.
As the temperature of a liquid increases, its density decreases whilst as the pressure of a gas increases, its density increases. At the critical point, the density of both phases becomes the same so that the two phases are indistinguishable. By xe2x80x9cin a subcritical statexe2x80x9d we mean that the high pressure liquefied gas will not be become xe2x80x9csupercriticalxe2x80x9d i.e. be above both its critical temperature and pressure (as determined from the phase diagram of the gas) under all useful operating conditions of the apparatus. For example the pressure of the liquefied gas will not be so great that the gas becomes supercritical at a temperature below say 30xc2x0 C.
Whilst the critical temperature and pressure are documented for particular gases, for example:
these values will tend to be modified by the presence of other components in a formulation containing the liquefied gas.
Gases considered to be especially suitable for carrying out the method of the current invention include carbon dioxide, nitrous oxide and sulphur hexafluoride. Carbon dioxide and nitrous oxide are the preferred gases, especially carbon dioxide. Mixture of such gases may also be used. Such gases do not deplete atmospheric ozone, act as good solvent or suspension media, provide good propellant characteristics for droplet or particle cloud generation, and reduce the need for excipients, especially co-solvents.
Carbon dioxide in liquefied form behaves as a particularly good solvent so that surface active agents to stabilise suspensions may be dissolved therein without the need for additional co-solvents. Furthermore, upon expansion into the atmosphere it undergoes substantially instantaneous flash evaporation giving rise to an aerosol mist of the active ingredient with very small particle sizes.
Substances suitable for delivery in this way include pharmaceuticals especially pharmaceuticals destined for inhalation such as salbutamol, beclomethasone dipropionate, salmeterol and fluticasone propionate and pharmaceutically acceptable salts thereof. Other pharmaceuticals destined for inhalation include cromoglycate, nedocromil, ipratropium, terbutaline, formoterol, budesonide and reproterol and pharmaceutically acceptable salts thereof.
Depending on the properties of the active ingredient and its solubility or otherwise in the liquefied gas propellant, excipients might be used to improve the formulation characteristics.
In order to improve the properties of a suspension formulation it may be desired to dissolve or disperse a surfactant in the liquefied gas. A co-solvent may likewise be included in the liquefied gas in order to improve the properties of solution or suspension formulations. As to whether a suspension or solution of the substance to be dispensed may be preferred and the concentrations thereof as well as the use and concentrations of excipients such as co-solvents, surfactants or diluents will depend on the solubility and other properties of the substance to be dispensed in the propellant.
Preferred embodiments of the invention are described below, by example only, with reference to the accompanying drawings, wherein: